title: Sporadic inclusion-body myositis: conformational multifactorial ageing-related degenerative muscle disease associated with proteasomal and lysosomal inhibition, endoplasmic reticulum stress, and accumulation of amyloid-β42 oligomers and phosphorylated tau.
abstract: The pathogenesis of sporadic inclusion-body myositis (s-IBM), the most common muscle disease of older persons, is complex and multifactorial. Both the muscle fiber degeneration and the mononuclear-cell inflammation are components of the s-IBM pathology, but how each relates to the pathogenesis remains unsettled. We consider that the intramuscle fiber degenerative component plays the primary and the major pathogenic role leading to muscle fiber destruction and clinical weakness. In this article we review the newest research advances that provide a better understanding of the s-IBM pathogenesis. Cellular abnormalities occurring in s-IBM muscle fibers are discussed, including: several proteins that are accumulated in the form of aggregates within muscle fibers, including amyloid-β42 and its oligomers, and phosphorylated tau in the form of paired helical filaments, and we consider their putative detrimental influence; cellular mechanisms leading to protein misfolding and aggregation, including evidence of their inadequate disposal; pathogenic importance of endoplasmic reticulum stress and the unfolded protein response demonstrated in s-IBM muscle fibers; and decreased deacetylase activity of SIRT1. All these factors are combined with, and perhaps provoked by, an ageing intracellular milieu. Also discussed are the intriguing phenotypic similarities between s-IBM muscle fibers and the brains of Alzheimer and Parkinson's disease patients, the two most common neurodegenerative diseases associated with ageing. Muscle biopsy diagnostic criteria are also described and illustrated.
authors.affiliation: University of Southern California Keck School of Medicine, Good Samaritan Hospital, USC Neuromuscular Centre, Department of Neurology, Los Angeles, CA 90017, USA. askanas@usc.edu
authors.forename: Valerie
authors.initials: V
authors.lastname: Askanas
authors.forename: W King
authors.initials: WK
authors.lastname: Engel
mesh_terms: D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology; D001706:Biopsy; D004721:Endoplasmic Reticulum / Q000473:pathology / Q000502:physiology*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D008854:Microscopy, Electron; D018485:Muscle Fibers, Skeletal / Q000473:pathology / Q000502:physiology*; D009132:Muscles / Q000473:pathology / Q000503:physiopathology; D018979:Myositis, Inclusion Body / Q000473:pathology / Q000503:physiopathology*; D055435:Myostatin / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011487:Protein Conformation; D057165:Proteostasis Deficiencies / Q000473:pathology / Q000503:physiopathology; D056564:Sirtuin 1 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; C054369:MAPT protein, human; D055435:Myostatin; D010446:Peptide Fragments; D051844:alpha-Synuclein; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex; C447939:SIRT1 protein, human; D056564:Sirtuin 1